Differently from acute pain, which exerts an important physiological action alerting the organism towards an incoming danger or damage, chronic pain is not involved in any protective action.
Chronic pain may be divided in two main categories: chronic inflammatory pain and neuropathic pain. The latter is due to a direct lesion on the nervous pathways by the noxa, which can be infectious, metabolic, vascular or other. In chronic inflammatory pain the lesioned tissues release algogenic factors which in turn damage nerve terminals creating a vicious mechanism which maintains and potentiates the perception of pain (hyperalgesia) or transforms into pain other types of perception (allodynia).
Chronic pain, of both neuropathic and inflammatory origin, is an important epidemiologic aspect of a high unmet medical need condition; in fact this is a therapeutic area presently characterized by modestly effective and poorly tolerated treatments.
An increasing number of patients suffer from iatrogenic neuropathic pain, induced by anti-tumor therapies used in modern oncology. In particular taxol derived drugs, cisplatin and vincristine are among the drugs which more often induce painful neuropathies. Currently no effective and/or well tolerated treatments exist for this kind of pain. In fact classical antiepileptic or antidepressive agents successfully used in other forms of neuropathic pain, such as lamotrigine (Renno S. I. 2006, J. Clin. Oncol. ASCO Annual Meeting Proceeding Part I vol. 24, No 18S:8530), gabapentin (Wong G. Y. 2005, J. Clin. Oncol. ASCO Annual Meeting Proceeding Part I vol. 23, No 16S:8001) or nortriptyline (Hammack J. E. 2002, Pain 98:195-203) are absolutely unsatisfactory on the basis of their therapeutic index.
Nucleoside analogue reverse transcriptase inhibitors (ddC, d4T, AZT) are commonly used as antiviral drugs in the treatment of AIDS. These drugs often cause the insurgence of peripheral neuropathies with different degrees of severity after prolonged treatment. As in the case of chemotherapeutic agents, these symptoms may be so strong to induce shortening or suspension of these life-saving therapies. The patterns of these neuropathies are clearly different from those induced by the progression of AIDS; they are in fact characterized by the sudden onset of very intense burning discomfort in both hands and feet at about the tenth week of treatment. HIV-induced neuropathies, on the contrary, have a very slow progression (Dubinsky R. M. 1989, Muscle Nerve 12:856-860). As for chemotherapy-induced neuropathies, it is difficult to treat this kind of pain.
The tricyclic antidepressant amitryptiline and the sodium channel blocker mexiletine, effective on various forms of painful peripheral neuropathies, did not show any significant effect on this kind of neuropathic pain (Kieburtz K. 1998 Neurology 51:1682-1688). Gabapentin showed some efficacy, although patients with severe syndromes rarely reach satisfactory results and the additional administration of narcotics is required (McArthur J. C. 2001, The Hopkins HIV report. http://www.hopkins-aids.edu/publications/report/may01—2.html).
Other forms of neuropathic pain may be caused by viral infections. Postherpetic neuralgia, for instance, is caused by the reactivation, long after the infection, of the varicella-zoster virus. This kind of neuropathy is characterized by the development of strong mechanical allodynia, frequent loss of sensitivity towards thermal stimuli and spontaneous intermitting pain. Pain intensity compromises the quality of life of patients suffering from this condition.
Of high epidemiological relevance is the pain referred to as cephalalgia. This is localized to the head, face and neck. When cephalea occurs in a paroxystic way, with recurrent episodes lasting from hours to days and is associated to general sickness, it is called migraine. Several forms of migraine are recognized such as common, classical, hemiplegic, vertebro-basilar, etc.
The current treatment for migraine entails the use of different kinds of analgesic agents, from non-steroidal anti-inflammatory drugs (NSAIDs) to opioids, antihistaminic drugs and ergotamine derivatives. In the last decade triptan 5HT2 antagonists have been used; they are often able to block an attack at its insurgence, if promptly administered. All these treatments show serious limits in terms of both efficacy and tolerability. In the most severe cases, in which painful attacks recur many times a week, a pre-emptive therapy with antiepileptic, beta blocker and antidepressant drugs is performed. The maximum result which can be achieved with these pre-emptive therapies is 50% reduction in the frequency and intensity of the painful attacks, but not their definitive remission.
Inflammatory pain is another form of chronic pain. It is caused by the release of mediators which either directly activate the nociceptors localized on primary afferents, or lower their activation threshold, thus increasing their sensitivity to either painful or non-painful stimuli of different nature. Excited primary afferents may in turn release neurotransmitters which can stimulate immune cells recruited by the inflammatory process causing the release of additional inflammatory mediators.
This phenomenon, defined ‘neurogenic inflammation’, leads to an autoamplification of the symptomatology of the patient. Osteoarthritis is a particularly severe and painful form of this kind of pathology. Osteoarthritis is a form of degenerative arthritis causing the breakdown and eventual loss of the cartilage of one or more joints. The most common symptom related to this pathology is pain in the affected joint after repetitive use or after prolonged periods of inactivity (night and rest pain). Even if a certain correlation between pain and the extension of the damage at the joint has been demonstrated, the precise etiology of this kind of pain is still obscure; in fact, patients with relatively small damages at the joints suffer from very intense pain and viceversa; this finding suggests that it is not a merely inflammatory pain, but that a neuropathic component is present as well. Recommended treatments include NSAIDs, steroids and opioids, but the use of these drugs is associated with the insurgence of severe side-effects; in addition, they do not show full efficacy in many instances (Altman R. D. 2000 Arthritis Rheum. 43:1905-1915).
The fibromyalgia syndrome is the most frequent cause of chronic, widespread pain, associated with auxiliary symptoms, such as sleep disturbances and chronic fatigue (Rao S. G. 2007, Psychopharmacol. Bull. 40:24-67). Nearly 2% of the general population in the United States suffers from fibromyalgia, with females of middle age being at increased risk. Patients with fibromyalgia display quantitative abnormalities in pain perception under experimental conditions, in the form of both allodynia and hyperalgesia: these data are suggestive of a state of sensitized pain perception.
Recently, pregabalin and duloxetine showed some efficacy in clinical trials for the treatment of the muscle pain in fibromyalgia (Crofford L. J. 2005, Arthritis Rheum. 52:1264-1273; Maizels M. 2005, Am. Fam. Physician 71:483-490). Nonetheless, at present, the medical treatment for pain relief in fibromyalgia is unsatisfactory (Offenbaecher M. 2005, CNS Spectr. 10:285-297) and fibromyalgia represents a high unmet medical need.
Dimiracetam (2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole) is a bicyclic pyrrolidinonic derivative of formula (I)

Patent application EP-A-335483 claims its pharmaceutical use as a nootropic agent, i.e. able to improve learning and memory in humans and animals. Dose-response data show that the nootropic activity of dimiracetam tends to lower for oral doses greater than 10 mg/kg (J. Med. Chem., 1993, 36:4214-4220). Patent application WO-A-93/09120 claims a process for the preparation of dimiracetam and of its enantiomers.
WO-A-2004/085438 claims a set of derivatives of 2,5-dioxohexahydro-1H-pyrrolo[1,2-a]imidazole; a typical feature of these compounds is the presence, in position 3 of the imidazole ring, of an aromatic carbocyclic or heterocyclic ring; these compounds, notwithstanding their utility in the treatment of painful conditions, show a therapeutic index which is not fully satisfactory.
In view of the above mentioned background the need is felt for new drugs endowed with high antihyperalgesic and antiallodynic activity towards chronic pain, and characterized by a high therapeutic index. The need is also felt for the treatment of specific forms of neuropathic pain which are not well treated with traditional antihyperalgesic agents.